Glycogen Storage Disease Type II Pompe Disease Clinical Trial
— NEO-EXTOfficial title:
An Open-label, Multicenter, Multinational Extension Study of the Long-term Safety and Pharmacokinetics of Repeated Biweekly Infusions of Avalglucosidase Alfa (neoGAA, GZ402666) in Patients With Pompe Disease
| Verified date | February 2024 |
| Source | Sanofi |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
Primary Objective: Long-term safety and pharmacokinetics (PK) of avalglucosidase alfa Secondary Objective: Long-term effect of avalglucosidase alfa on pharmacodynamic variables
| Status | Completed |
| Enrollment | 19 |
| Est. completion date | December 12, 2022 |
| Est. primary completion date | December 12, 2022 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | N/A and older |
| Eligibility | Inclusion criteria: Participants with Pompe disease who previously completed an avalglucosidase study. The participant and/or their parent/legal guardian is willing and able to provide signed informed consent, and the participant, if <18 years of age, was willing to provide assent if deemed able to do so. The participant (and participant's legal guardian if participant is <18 years of age) must have had the ability to comply with the clinical protocol. The participant, if female and of childbearing potential, had to have a negative pregnancy test [urine beta-human chorionic gonadotropin] at baseline. Exclusion criteria: The participant was concurrently participating in another clinical study using investigational treatment. The participant, in the opinion of the Investigator, was unable to adhere to the requirements of the study. The participant had clinically significant organic disease (with the exception of symptoms relating to Pompe disease), including clinically significant cardiovascular, hepatic, pulmonary, neurologic, or renal disease, or other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, precluded participation in the study or potentially decreases survival. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial. |
| Country | Name | City | State |
|---|---|---|---|
| Belgium | Investigational Site Number 056001 | Leuven | |
| Denmark | Investigational Site Number 208001 | København Ø | |
| France | Investigational Site Number 250003 | Nice | |
| France | Investigational Site Number 250002 | Paris | |
| Germany | Investigational Site Number 276003 | Mainz | |
| Germany | Investigational Site Number 276001 | München | |
| Germany | Investigational Site Number 276002 | Münster | |
| Netherlands | Investigational Site Number 528001 | Rotterdam | |
| United Kingdom | Investigational Site Number 826003 | Newcastle Upon Tyne | |
| United States | Investigational Site Number 840011 | Cincinnati | Ohio |
| United States | Investigational Site Number 840009 | Dallas | Texas |
| United States | Investigational Site Number 840002 | Durham | North Carolina |
| United States | Investigational Site Number 840003 | Fairfax | Virginia |
| United States | Investigational Site Number 840010 | Jacksonville | Florida |
| United States | Investigational Site Number 840001 | Kansas City | Kansas |
| United States | Investigational Site Number 840006 | Phoenix | Arizona |
| United States | Investigational Site Number 840008 | Saint Louis | Missouri |
| Lead Sponsor | Collaborator |
|---|---|
| Genzyme, a Sanofi Company |
United States, Belgium, Denmark, France, Germany, Netherlands, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), Infusion Associated Reactions (IARs) and Deaths | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An serious AE (SAE) is any untoward medical occurrence that results: death or life-threatening or inpatient hospitalization or prolongation of existing hospitalization or persistent or significant disability or congenital anomaly or medically important event. TEAEs are defined as AEs that develop or worsen during the on-treatment period (that is, from the time of first dose of IMP up to 4 weeks after the last administration of the IMP). Protocol-defined IARs were defined as AEs that occur during either the infusion or the post-infusion observation period (that is, up to 2 hours or longer following the infusion as per the Investigator's discretion) which were deemed to be related or possibly related to the IMP. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Number of Participants With Clinically Significant Physical Examination Abnormalities | Physical examination included, at a minimum, an assessment of the participant's general appearance; skin; head, eyes, ears, nose, and throat; examinations of lymph nodes, abdomen, extremities/joints, neurological and mental status; heart and respiratory auscultation; peripheral arterial pulse; and pupil, knee, achilles, and plantar reflexes. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Number of Participants With Potentially Clinically Significant Abnormalities in Biochemistry | Blood samples were collected to determine the clinical chemistry laboratory abnormalities. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Number of Participants With Potentially Clinically Significant Abnormalities in Hematology | Blood samples were collected to determine the hematology laboratory significant abnormalities. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Change From Baseline in Urine BUN up to Last IMP Administration | Last on-treatment (LOT) values were collected at or just prior to the last IMP administration. | Baseline (Day 1) and last on-treatment values (up to 454 weeks) | |
| Primary | Change From Baseline in Urine Hyaline Casts up to Last IMP Administration | The LOT values were collected at or just prior to the last IMP administration. | Baseline (Day 1) and last on-treatment values (up to 454 weeks) | |
| Primary | Change From Baseline in Urine Leukocytes [White Blood Cell (WBC)] up to Last IMP Administration | The LOT values were collected at or just prior to the last IMP administration. | Baseline (Day 1) and last on-treatment values (up to 454 weeks) | |
| Primary | Change From Baseline in Urine Specific Gravity up to Last IMP Administration | The LOT values were collected at or just prior to the last IMP administration. | Baseline (Day 1) and last on-treatment values (up to 454 weeks) | |
| Primary | Change From Baseline in Urine pH up to Last IMP Administration | The LOT values were collected at or just prior to the last IMP administration. | Baseline (Day 1) and last on-treatment values (up to 454 weeks) | |
| Primary | Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities | Participants vital signs were examined to determine the abnormalities. Vital signs included heart rate, systolic and diastolic blood pressure. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Number of Participants With Body Weight Increased/Decreased | Body weight was measured in kilograms and collected in the electronic case report forms every 3 months throughout the duration of the study, as well as at the end of study visit. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Number of Participants With Potentially Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | Standard 12-lead ECGs were recorded after at least 15 minutes in the supine position using an electrocardiographic device. The following were assessed: heart rate, rhythm, interval between the peaks of successive QRS complexes (RR), interval from the beginning of the P wave until the beginning of the QRS complex (PR), interval from start of the Q wave to the end of the S wave (QRS), interval between the start of the Q wave and the end of the T wave (QT), QT interval corrected for heart rate (QTc) automatic correction evaluation (by the ECG device), QRS axis, R voltage V6, voltage V1, left ventricular hypertrophy criteria, right ventricular hypertrophy criteria, repolarization charges, and overall cardiac impression for each participant. | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Number of Participants With Antidrug Antibodies (ADA) Status, Positive or Negative | ADA negative was defined as ADAs are not detected (that is, negative in screening assay or reactive in screening but negative in confirmatory assay). ADA positive was defined as ADA was detected (that is, an assay signal equal to or greater than the cut-point in the screening assay and was tested positive in the confirmatory assay). | From first dose of IMP up to 4 weeks after the last treatment administration of the IMP, a maximum up to 458 weeks | |
| Primary | Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa | Cmax was defined as maximum plasma concentration observed. The non-compartmental pharmacokinetic (PK) analysis was performed. | Predose (prior to infusion), end of the infusion and at 1, 4, 8, 12, and 24 hours post-dose on Week 312 | |
| Primary | Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Real Time (AUClast) of Avalglucosidase Alfa | AUClast was calculated using the trapezoidal method from time zero to the real time. The non-compartmental PK analysis was performed. | Predose (prior to infusion), end of the infusion and at 1, 4, 8, 12, and 24 hours post-dose on Week 312 | |
| Primary | Time Corresponding to the Last Concentration (Tlast) of Avalglucosidase Alfa | Tlast was defined as time corresponding to the last concentration above the limit of quantification, Clast. The non-compartmental PK analysis was performed. | Predose (prior to infusion), end of the infusion and at 1, 4, 8, 12, and 24 hours post-dose on Week 312 | |
| Primary | Terminal Half-Life (t1/2z) of Avalglucosidase Alfa | t1/2z was calculated according to the following equation: t1/2z = 0.693/?z. Where, ?z is the slope of the regression line of the terminal phase of the plasma concentration versus time curve. Half-life was calculated by taking the regression of at least 3 points. The non-compartmental PK analysis was performed. | Predose (prior to infusion), end of the infusion and at 1, 4, 8, 12, and 24 hours post-dose on Week 312 | |
| Primary | Apparent Total Body Clearance Steady-State (CLss) of Avalglucosidase Alfa | CLss was calculated using the following equation: CLss= dose/AUC. The non-compartmental PK analysis was performed. | Predose (prior to infusion), end of the infusion and at 1, 4, 8, 12, and 24 hours post-dose on Week 312 | |
| Primary | Apparent Volume of Distribution Steady-State (Vss) of Avalglucosidase Alfa | Vss was calculated using the following equation: Vz= CLss/?z. The non-compartmental PK analysis was performed. | Predose (prior to infusion), end of the infusion and at 1, 4, 8, 12, and 24 hours post-dose on Week 312 | |
| Secondary | Change From Baseline in Cross-Sectional Area (CSA) of Skeletal Muscle Magnetic Resonance Imaging (MRI) Up to Week 442 | Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The measured area of each muscle group, CSA was provided. | Baseline (Day 1) and Weeks 104 and 442 | |
| Secondary | Change From Baseline in Dixon Fat Fraction of Skeletal Muscle Magnetic Resonance Imaging (MRI) Up to Week 442 | Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). Three-point dixon imaging provided quantification of fat content in muscles [fat fraction (FF)]. | Baseline (Day 1) and Weeks 104 and 442 | |
| Secondary | Change From Baseline in Index of Real Muscle Mass (IRMM) of Skeletal Muscle Magnetic Resonance Imaging (MRI) Up to Week 442 | Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The FF was combined with the CSA measurements trophicity to provide an IRMM in mm^2 (that is, IRMM = CSA x [1 - FF]). A negative change from baseline value in IRMM of skeletal muscle MRI indicates muscle loss (worse outcome) and a positive change from baseline value indicates muscle gain (better outcome). | Baseline (Day 1) and Weeks 104 and 442 | |
| Secondary | Change From Baseline in T2 of Skeletal Muscle Magnetic Resonance Imaging (MRI) Up to Week 442 | Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The T2 multi-slice multi-spin echo and B1 mapping provided a quantitative measure of disease activity (edema, inflammation) within muscles. | Baseline (Day 1) and Weeks 104 and 442 | |
| Secondary | Change From Baseline in T2 With B1 of Skeletal Muscle Magnetic Resonance Imaging (MRI) Up to Week 442 | Skeletal muscle MRI performed prior to the muscle needle or open biopsy procedure using both qualitative (T1) and quantitative (T2, dixon) modalities to assess disease severity and detect treatment effects. The T1 weighted axial data was analyzed using the mercuri scale, which determines degree of intact muscle and fatty replacement, providing a qualitative measure of overall disease severity. Trophicity changes were evaluated for 5 muscle groups, including the upper leg muscles (quadriceps, hamstring) and the lower leg muscles (triceps, extensors, fibularis). The T2 multi-slice multi-spin echo and B1 mapping provided a quantitative measure of disease activity (edema, inflammation) within muscles. | Baseline (Day 1) and Weeks 104 and 442 | |
| Secondary | Change From Baseline in Skeletal Muscle Biopsy Up to Week 312 | Skeletal muscle needle or open biopsy was performed on the lower extremity (quadriceps) muscle to assess glycogen content. The MRI appearance of the muscle was used to determine the level (axial slice position) that the biopsy procedure should target (avoiding fatty replaced tissue). Glycogen content was measured by histomorphometric analysis or severity grading to determine how effectively avalglucosidase alfa was able to remove glycogen from muscle. | Baseline (Day 1) and Weeks 27, 104, 208, 260 and 312 | |
| Secondary | Change From Baseline in Urinary Glucose Tetrasaccharide (Hex4) Level Up to Week 442 | The Hex4, a tetraglucose oligomer, has been shown to be elevated in the urine of participants with Pompe disease. Hence, determination of Hex4 levels may be a means by which the efficacy of treatments were monitored. Urine samples were collected prior to IMP infusion for the assessment of urinary Hex4 concentrations. | Baseline (Day 1) and Weeks 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 338, 364, 390, 416 and 442 |